Host test based on tumor necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein-10 and C-reactive protein for differentiating bacterial and viral respiratory tract infections in adults: diagnostic accuracy study.

OBJECTIVES: To assess the performance of a test (called BV), integrating the blood levels of three immune proteins into a score, to differentiate bacterial from viral infection among adults with suspected lower respiratory tract infection (LRTI). METHODS: Prospective diagnostic accuracy study, enrolling febrile adults >18 years with LRTI signs or symptoms for less than 7 days presenting to several hospitals' emergency departments in Israel. The main exclusion criterion was immunodeficiency. Reference standard diagnosis (bacterial/viral/indeterminate) was based on three experts independently reviewing comprehensive patient data including follow-up data. BV generated three results: viral infection or other nonbacterial condition (0 ≤ score < 35), equivocal (35 ≤ score ≤ 65) and bacterial infection including co-infection (65 < score ≤ 100). BV performance was assessed against the reference standard with indeterminate reference standard and equivocal BV cases removed. RESULTS: Of 490 enrolled patients, 415 met eligibility criteria (median age 56 years, interquartile range 35). The reference standard classified 104 patients as bacterial, 210 as viral and 101 as indeterminate. BV was equivocal in 9.6% (30/314). Excluding indeterminate reference standard diagnoses and equivocal BV results, BV's sensitivity for bacterial infection was 98.1% (101/103; 95% confidence interval 95.4-100), specificity 88.4% (160/181; 83.7-93.1) and negative predictive value 98.8% (160/162; 97.1-100). DISCUSSION: BV exhibited high diagnostic performance for febrile adults with suspected LRTI among patients with reference standard diagnoses of bacterial or viral LRTI.

In Vitro Pharmacodynamics of a Novel Ceftibuten-Clavulanate Combination Antibiotic against Enterobacteriaceae.

A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the ß-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those caused by extended-spectrum-ß-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (∼59% free time above the CTB-CLA MIC) against ESBL-producing Escherichia coli and Klebsiella pneumoniae (CTB-CLA MICs of 0.25/0.125 to 1/0.5 µg/ml) using the in vitro chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (fT>threshold) to be the best pharmacodynamic index (R2 = 0.85) compared with the free area under the curve (AUC)/threshold ratio (R2 = 0.62) and free maximum concentration/threshold ratio (R2 = 0.37). For E. coli isolates, stasis and 1-log10 CFU reductions were achieved at 30.9 and 47.9% fT>CTB concentrations of the 2:1 CTB-CLA MIC (fT>MIC here), respectively. For K. pneumoniae isolates, stasis and 1-log10 CFU reductions were achieved at 51.9 and 92.0% fT>MIC, respectively. These data inform exposure requirements for CLA combined with CTB for optimizing pharmacodynamics against Enterobacteriaceae and should be useful in designing dosage regimens for this combination antibiotic.

Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function.

OBJECTIVES: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. METHODS: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 µg/mL was compared between proposed and standard regimens. RESULTS: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. CONCLUSION: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 µg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

Effects of Clinically Meaningful Concentrations of Antipseudomonal ß-Lactams on Time to Detection and Organism Growth in Blood Culture Bottles.

The effectiveness of antimicrobial binding resins present in blood culture (BC) bottles in removing meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam is unknown. We assessed the time to detection (TTD) and growth of 2 Pseudomonas aeruginosa isolates in the presence of clinically meaningful concentrations of these antibiotics. Bactec Plus Aerobic/F and BacT/Alert FA Plus BC bottles were inoculated with one of two isolates (1 meropenem susceptible and 1 resistant), followed by fresh whole blood containing the peak, midpoint, or trough plasma concentrations for meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam. Matching bottles were loaded into their respective detection instruments and a standard incubator at 37°C, with TTD and CFU being monitored for up to 72 h. Bacterial growth was observed for 11/48 (22.9%), 22/48 (45.8%), and 47/48 (97.9%) of all BC bottles inoculated with the peak, midpoint, and trough concentrations, respectively (P ≤ 0.001). When P. aeruginosa was isolated, the TTD was typically <26 h, and no differences between Bactec and BacT/Alert bottles were observed. In both systems, meropenem was removed to a greater degree than were ceftolozane and ceftazidime; however, concentrations for all antibiotics remained above the MIC for the susceptible organisms at 12 h. BC bottles containing antibiotic binding resins may not sufficiently inactivate achievable concentrations of meropenem, ceftolozane-tazobactam, and ceftazidime-avibactam. The consistent identification of both P. aeruginosa isolates was observed only in the presence of antibiotic trough concentrations. To minimize false-negative BC results for patients already receiving these antibiotics, cultures should be collected just prior to the next dose, when antibiotic concentrations are lowest.

Antibacterial activity of human simulated epithelial lining fluid concentrations of amikacin inhale alone and in combination with meropenem against Acinetobacter baumannii.

BACKGROUND: Acinetobacter baumannii(ACBN) is a MDR organism causing pneumonia in ventilated patients. High MICs often result in insufficient lung exposures, thus poor outcomes have been observed with parenteral antimicrobials. Amikacin Inhale(AMK-I), is a drug-device combination of amikacin and a Pulmonary Drug Delivery System device. We aimed to describe the pharmacodynamic profile of human simulated epithelial lining fluid(ELF) exposures of AMK-I and intravenous meropenem alone and in combination against ACBN with variable susceptibility profiles. METHODS: AMK-I ELF exposures and the ELF profile of meropenem achieved after intravenous administration were evaluated in an in vitro pharmacodynamic model. Nine ACBN with amikacin/meropenem MICs of 2-512/2 to >64 mg/L were utilized. MICs were repeated post exposure to assess the development of resistance. RESULTS: AMK-I monotherapy rapidly achieved and sustained bactericidal activity for isolates with amikacin MIC ≤128 mg/L. For isolates with MICs of 256 and 512 mg/L initial reductions in bacterial density were observed followed by regrowth. The combination produced similar bactericidal activity against ACBN with amikacin MICs of ≤128. While the combination regimen produced initial reductions and prolonged the duration of activity against organisms with MICs of 256 and 512 mg/L, regrowth and MIC elevations were noted during the 72-h exposure period. CONCLUSION: The combination achieved rapid and sustained efficacy when amikacin MICs were ≤128 mg/L and prolonged the duration of activity compared to monotherapy for organisms with MICs 256 mg/L and 512 mg/L. These data support the utility of AMK-I as an adjunct for the treatment of pneumonia caused by A. baumannii with MICs above current susceptibility break-points.

Multicenter Evaluation of Ceftazidime-Avibactam and Ceftolozane-Tazobactam Inhibitory Activity against Meropenem-Nonsusceptible Pseudomonas aeruginosa from Blood, Respiratory Tract, and Wounds.

The recent escalation of occurrences of carbapenem-resistant Pseudomonas aeruginosa has been recognized globally and threatens to erode the widespread clinical utility of the carbapenem class of compounds for this prevalent health care-associated pathogen. Here, we compared the in vitro inhibitory activity of ceftazidime-avibactam and ceftolozane-tazobactam against 290 meropenem-nonsusceptible Pseudomonas aeruginosa nonduplicate clinical isolates from 34 U.S. hospitals using reference broth microdilution methods. Ceftazidime-avibactam and ceftolozane-tazobactam were active, with ceftolozane-tazobactam having significantly higher inhibitory activity than ceftazidime-avibactam. The heightened inhibitory activity of ceftolozane-tazobactam was sustained when the site of origin (respiratory, blood, or wound) and nonsusceptibility to other ß-lactam antimicrobials was considered. An extensive genotypic search for enzymatically driven ß-lactam resistance mechanisms revealed the exclusive presence of the VIM metallo-ß-lactamase among only 4% of the subset of isolates nonsusceptible to ceftazidime-avibactam, ceftolozane-tazobactam, or both. These findings suggest an important role for both ceftazidime-avibactam and ceftolozane-tazobactam against carbapenem-nonsusceptible Pseudomonas aeruginosa Further in vitro and in vivo studies are needed to better define the clinical utility of these novel therapies against the increasingly prevalent threat of multidrug-resistant Pseudomonas aeruginosa.

Anti-staphylococcal activity resulting from epithelial lining fluid (ELF) concentrations of amikacin inhale administered via the pulmonary drug delivery system.

BACKGROUND: Amikacin inhale (BAY41-6551), a unique drug-device combination of a specially formulated drug solution and a pulmonary drug delivery system device (AMK-I) is currently under phase III study as an adjunctive therapy to IV antibiotics for the treatment of Gram-negative pneumonia in mechanically ventilated patients. While the epidemiology of nosocomial pneumonia is predominated by Gram-negative pathogens such as Pseudomonas aeruginosa and the Enterobacteriaceae, Staphylococcus aureus is increasingly recognized as a pathogen of concern for these pulmonary based infections. Since the aminoglycosides are historically quite active against S. aureus the use of adjunctive AMK-I may enhance bacterial eradication. Herein, we aimed to characterize the in vitro pharmacodynamic (PD) profile of human-simulated ELF exposures of AMK-I against both methicillin-sensitive (MSSA) and -resistant (MRSA) S. aureus. METHODS: An in vitro model was used to simulate the resultant ELF pharmacokinetic profile of amikacin after the administration of AMK-I 400 mg q12h. The antibacterial activity of this regimen was tested against 7 S. aureus isolates that display MIC profiles encountered clinically (4 MRSA; MIC range 4-64, 3 MSSA; MIC range 8-16 mg/L). Experiments were conducted over 24 h and samples were taken throughout this period to assess the bacterial density in both control and treatments. RESULTS: The mean ± SD inoculum 0 h bacterial density was 6.4 ± 0.09 which increased to 8.6 ± 0.19 log10 CFU/mL in the control models by the end of 24 h experiments. Simulated ELF concentrations of AMK-I resulted in a rapid, 5 log10 declined in CFU over the initial 12 h for all MRSA and MSSA isolates. After 12 h, all bacterial counts remained below the limit of detection (LOD, 1.7 log10 CFU/mL) and no regrowth was evident at the end of the study. CONCLUSION: AMK-I produced an ELF exposure profile that was rapidly bactericidal against S. aureus displaying typical MICs to amikacin irrespective of their phenotypic profile to methicillin. While the Gram-negative organisms are the target pathogens for AMK-I in the ongoing clinical trials, these data suggest that this adjunctive regimen may also have the potential to eradicate both MSSA and MRSA from lower airway which needs to be further evaluated in randomized-controlled clinical trials.

Obesity and skin and soft tissue infections: how to optimize antimicrobial usage for prevention and treatment?

PURPOSE OF REVIEW: Skin and soft tissue infections (SSTIs) are prevalent in the obese population, with rising trend expected. Although numerous antibiotics are available for the prevention and treatment of SSTIs, their characterization in obese patients is not a regulatory mandate. Consequently, information that carries importance for optimizing the dosing regimen in the obese population may not be readily available. This review focuses on the most recent pharmacokinetic and pharmacodynamic data on this topic with attention to cefazolin for surgical prophylaxis as well as antibiotics that are active against methicillin-resistant Staphylococcus aureus (MRSA). Moreover, the implications for optimizing SSTIs prevention and treatment in the obese population will also be discussed. RECENT FINDINGS: On the basis of pharmacokinetic/pharmacodynamic considerations, most studies found a perioperative prophylactic cefazolin regimen of 2 g to be reasonable in the case of obese patients undergoing cesarean delivery or bariatric surgery. There is general paucity of data regarding the pharmacokinetic/pharmacodynamic characteristics of antimicrobials active against MRSA in obese patients, especially for the target tissue. Therapeutic drug monitoring has been correlated with pharmacokinetic/pharmacodynamic optimization for vancomycin and teicoplanin, and should be used in these cases. There is more supportive evidence for the use of oxazolidinones (linezolid and tedizolid), daptomycin and lipoglycopeptides (telavancin, dalbavancin and oritavancin) in the management of SSTIs in this population. SUMMARY: The pharmacokinetic/pharmacodynamic approach, which can be used as a basis or supplement to clinical trials, provides valuable data and decision-making tools for optimizing regimens used for both prevention and treatment of SSTIs in the obese population. Important pharmacokinetic/pharmacodynamic characteristics of antibiotics, such as the penetration into the subcutaneous tissue and the probability of reaching the pharmacodynamic, target dictate efficacy, and thus should be taken into account and further investigated.

Population Pharmacokinetics of Cefazolin in Serum and Adipose Tissue From Overweight and Obese Women Undergoing Cesarean Delivery.

The optimal antibiotic prophylaxis dosing regimen of cefazolin for cesarean delivery (CD) in overweight and obese women is unknown. This study was done to compare the duration that cefazolin concentrations remain above the minimum inhibitory concentration (MIC) in adipose tissue (AT). Serum and AT concentrations from 3 previous studies in CD patients were comodeled using the nonparametric adaptive grid algorithm in Pmetrics. AT concentrations for 5000 overweight and obese patients receiving 1-, 2-, and 3-g cefazolin regimens were simulated to calculate the probability that free drug concentrations remained above an MIC of 2 µg/mL at 1, 1.5, and 2 hours after administration. Sixty-seven patients (mean body mass index 38.7 kg/m2 ; range 25.5-55.8 kg/m2 ) provided data. A 2-compartment model with 1 of the compartments representing AT fit the data best. Final model parameters were clearance 7.38 ± 5.34 L/h, volume of central compartment 11.8±9.36 L, and AT volume of distribution 80.12 ± 55.47 L. The mean±SD (median) penetration ratio of cefazolin into AT was 0.81 ± 2.06 (0.62). At 1.5 and 2 hours, 1-, 2-, and 3-g regimens achieved AT concentrations above the MIC in 71.2%, 92.4%, and 94.7%, and 55.7%, 86.8%, and 91.7%, respectively, of simulated patients. Cefazolin achieved good penetration into AT. Because CD duration is commonly less than 1.5 hours, a 2-g dose has a high probability of providing AT concentrations above the target pathogens' MIC for overweight and obese females. A second dose may be considered for longer surgeries.

Continuous and Prolonged Intravenous ß-Lactam Dosing: Implications for the Clinical Laboratory.

Beta-lactam antibiotics serve as a cornerstone in the management of bacterial infections because of their wide spectrum of activity and low toxicity. Since resistance rates among bacteria are continuously on the rise and the pipeline for new antibiotics does not meet this trend, an optimization of current beta-lactam treatment is needed. This review provides an overview of optimization through use of prolonged- and continuous-infusion dosing strategies compared with more traditional intermittent infusions. Included is an overview of the scientific basis for using these nontraditional prolonged- and continuous-infusion-based regimens, with a focus on major areas in which the clinical laboratory can support the clinical use of these regimens.

Attributable mortality of nosocomial Acinetobacter bacteremia.

OBJECTIVE: To determine the attributable mortality and outcome of nosocomial Acinetobacter bacteremia. DESIGN: Matched, retrospective cohort study. SETTING: Large, university-based, tertiary care center. PATIENTS: Of 219 patients with nosocomial Acinetobacter bacteremia identified by prospective surveillance during a 3-year period, 52 met the criteria for the study and were matched to a control patient by age, sex, primary and secondary diagnosis, operative procedures, and date of admission. RESULTS: A 100% success rate was achieved in the proportion of case patients and control patients matched for the compared criteria, except for major operative procedures (88%) and the presence of an important secondary underlying disease (54.5%). Twenty-nine (55.7%) of the case patients died, compared with 10 (19.2%) of the control patients (P<.001). The attributable mortality was 36.5% (95% CI, 27%-46%) and the risk ratio for death was 2.9 (95% CI, 1.58-5.32). In a multivariate survival analysis, older age, mechanical ventilation, renal failure, and Acinetobacter bacteremia (hazard ratio [HR], 4.41; 95% confidence interval [CI], 1.97-9.87; P<.001) were found to be independent predictors of mortality. There was a trend for a longer median duration of hospitalization among case patients, compared with control patients (11.5 vs. 6.5 days; P=.06). Three isolates were resistant to all but 1 antibiotic tested (colistin), and 45 isolates (86.5%) were resistant to 4 or more different antibiotic classes. CONCLUSIONS: When adjusted for risk-exposure time and severity of disease at admission, nosocomial Acinetobacter bacteremia is associated with mortality in excess of that caused by the underlying diseases alone.